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Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation
Development of an immune or autoimmune response involves T-cell activation in lymphoid organs and subsequent migration to peripheral tissues. Here we show that T-cell-specific ablation of the kinase TBK1 promotes T-cell activation but causes retention of effector T cells in the draining lymph node i...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Pub. Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302769/ https://www.ncbi.nlm.nih.gov/pubmed/25606824 http://dx.doi.org/10.1038/ncomms7074 |
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author | Yu, Jiayi Zhou, Xiaofei Chang, Mikyoung Nakaya, Mako Chang, Jae-Hoon Xiao, Yichuan William Lindsey, J. Dorta-Estremera, Stephanie Cao, Wei Zal, Anna Zal, Tomasz Sun, Shao-Cong |
author_facet | Yu, Jiayi Zhou, Xiaofei Chang, Mikyoung Nakaya, Mako Chang, Jae-Hoon Xiao, Yichuan William Lindsey, J. Dorta-Estremera, Stephanie Cao, Wei Zal, Anna Zal, Tomasz Sun, Shao-Cong |
author_sort | Yu, Jiayi |
collection | PubMed |
description | Development of an immune or autoimmune response involves T-cell activation in lymphoid organs and subsequent migration to peripheral tissues. Here we show that T-cell-specific ablation of the kinase TBK1 promotes T-cell activation but causes retention of effector T cells in the draining lymph node in a neuroinflammatory autoimmunity model, experimental autoimmune encephalomyelitis (EAE). At older ages, the T-cell-conditional TBK1-knockout mice also spontaneously accumulate T cells with activated phenotype. TBK1 controls the activation of AKT and its downstream kinase mTORC1 by a mechanism involving TBK1-stimulated AKT ubiquitination and degradation. The deregulated AKT-mTORC1 signalling in turn contributes to enhanced T-cell activation and impaired effector T-cell egress from draining lymph nodes. Treatment of mice with a small-molecule inhibitor of TBK1 inhibits EAE induction. These results suggest a role for TBK1 in regulating T-cell migration and establish TBK1 as a regulator of the AKT-mTORC1 signalling axis. |
format | Online Article Text |
id | pubmed-4302769 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Pub. Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-43027692015-03-20 Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation Yu, Jiayi Zhou, Xiaofei Chang, Mikyoung Nakaya, Mako Chang, Jae-Hoon Xiao, Yichuan William Lindsey, J. Dorta-Estremera, Stephanie Cao, Wei Zal, Anna Zal, Tomasz Sun, Shao-Cong Nat Commun Article Development of an immune or autoimmune response involves T-cell activation in lymphoid organs and subsequent migration to peripheral tissues. Here we show that T-cell-specific ablation of the kinase TBK1 promotes T-cell activation but causes retention of effector T cells in the draining lymph node in a neuroinflammatory autoimmunity model, experimental autoimmune encephalomyelitis (EAE). At older ages, the T-cell-conditional TBK1-knockout mice also spontaneously accumulate T cells with activated phenotype. TBK1 controls the activation of AKT and its downstream kinase mTORC1 by a mechanism involving TBK1-stimulated AKT ubiquitination and degradation. The deregulated AKT-mTORC1 signalling in turn contributes to enhanced T-cell activation and impaired effector T-cell egress from draining lymph nodes. Treatment of mice with a small-molecule inhibitor of TBK1 inhibits EAE induction. These results suggest a role for TBK1 in regulating T-cell migration and establish TBK1 as a regulator of the AKT-mTORC1 signalling axis. Nature Pub. Group 2015-01-21 /pmc/articles/PMC4302769/ /pubmed/25606824 http://dx.doi.org/10.1038/ncomms7074 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Yu, Jiayi Zhou, Xiaofei Chang, Mikyoung Nakaya, Mako Chang, Jae-Hoon Xiao, Yichuan William Lindsey, J. Dorta-Estremera, Stephanie Cao, Wei Zal, Anna Zal, Tomasz Sun, Shao-Cong Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation |
title | Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation |
title_full | Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation |
title_fullStr | Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation |
title_full_unstemmed | Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation |
title_short | Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation |
title_sort | regulation of t-cell activation and migration by the kinase tbk1 during neuroinflammation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302769/ https://www.ncbi.nlm.nih.gov/pubmed/25606824 http://dx.doi.org/10.1038/ncomms7074 |
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